Heavy metal tolerance and accumulation suggest that Populus nigra is suitable for phytoremediation. QTL mapping revealed the complex genetic architecture of cadmium response in this species and highlighted promising candidate genes. Poplar is promising for phytoremediation and a large phenotypic variation in response to Cd has been observed among and within Populus species. Scientific knowledge has increased regarding the physiological and molecular mechanisms of Cd response in poplars, however its genetic basis is still poorly understood. This study, investigated the genetic architecture of Cd accumulation and tolerance in Populus nigra L. A F1 progeny, grown in hydroponics under Cd treatment and control conditions, was analyzed by 21 phenotypic traits related to Cd tolerance, Cd accumulation, and chlorophyll fluorescence. These traits present a broad-sense heritability ranging from 0.22 to 0.57. Mapping of quantitative trait loci (QTL) revealed a total of 36 QTL for the female map and 21 QTL for the male map, corresponding to 12 and 11 genomic regions, respectively. The phenotypic variance explained by QTL ranged from 6.2 to 28.7 %, with an average of 14.5 %. Three main QTL cluster regions were defined on chromosomes IV and XIV. The projection of QTL intervals on the Populus trichocarpa Torr. & Gray annotated genome identified positional candidate genes (CGs), functionally related to the regulation of transcription, transport, response to oxidative stress, and the glutathione pathway. It was found that some CGs are directly related to Cd transport and detoxification, whereas other non-metal-specific CGs could also contribute to explain the phenotypic variation in Cd accumulation and tolerance. The high accumulation of Cd in roots and the relatively low translocation in leaves suggest that P. nigra would be a good candidate for the phytoremediation of metal-polluted sites.